Phase II PKC412 in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

• To investigate ASM/MCL-specific DNA mutations and compare gene expression changes in blood and bone marrow cells and in plasma for biomarker development before and during twice-daily oral dosing of PKC412 when administered to patients with ASM/MCL. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
• To investigate the effects of genetic variation in drug metabolism genes, disease related genes and drug target genes on patient response to twice-daily oral dosing of PKC412 when administered to patients with ASM/MCL. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
• To evaluate the safety and pharmacokinetics of twice-daily oral doses of PKC412 after a long term of treatment when administered to patients with ASM/MCL + AHNMD. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
• To evaluate the effect of PKC412 on survival after one year of treatment in ASM/MCL + AHNMD patients treated with PKC412. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

To evaluate the efficacy of twice-daily oral doses of PKC412 when administered to patients with ASM/MCL and AHNMD (associated hematological clonal non-mast cell lineage disease) by measuring response rate.

To evaluate the activity and safety profile of a novel investigational drug, PKC412, in patients with ASM/MCL. Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can release harmful substances, and can infiltrate tissues, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments such as interferon-alpha +/-, corticosteroids, and cladribine exhibit low response rates in advanced mast cell disease and are usually partial in nature.

• Mastocytosis, Systemic
• Leukemia, Mast-Cell

Inclusion Criteria:

• Histologically documented aggressive systemic mastocytosis or mast cell leukemia + AHNMD, regardless of the presence of absence of the D816V c-kit mutation, or the FIP1L1-PDGFR alpha fusion.
• Tissue for evaluation of KIT mutation status of the tumor cells must be collected and availability confirmed by PI within 6 months prior to entry into study (e.g. wild-type, D816V, or other KIT mutation). Patients who have systemic mastocytosis with eosinophilia and known positivity for the FIP1L1-PDGFR alpha fusion are also eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy.
• Karnofsky performance status of >30%.
• Liver enzyme values within normal limits unless the sole cause of liver elevation is due to ASM/MCL. Else, patients must have the following laboratory values: AST and ALT <= 4X ULN, and/or bilirubin <= 4X ULN if elevation of liver enzymes is considered solely due to ASM/MCL.
• Serum creatinine <2.0 mg/dL
• For patients with grade >2 blood values, the screening bone marrow exam (e.g. presence of mast cell infiltrate as defined in Appendix B) and/or the presence of disease-related hypersplenism should establish that the likely causes of these cytopenia(s) is related to ASM/MCL.
• No clinical or radiographic (by PA and lateral chest x-ray) evidence of active pulmonary disease which is considered by the investigator to be unrelated to mastocytosis.
• Patient must give written informed consent.

Exclusion Criteria:

• Female patients who are pregnant or breast-feeding, or any adult, male or female, of reproductive potential not agreeing to employ barrier contraceptives throughout the study.
• Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, are required to use barrier contraception for the duration of the study and for 3 months post study because of the long half life of the metabolite, CGP52421, and must avoid breast-feeding.
• Any other known disease, concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months, any Grade 3/4 cardiac problems as defined by the New York Heart Association Criteria and poorly controlled hypertension, chronic renal disease, active uncontrolled infection) which could compromise participation in the study.
• Known confirmed diagnosis of HIV infection or active viral hepatitis.
• Patients who have received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment.
• Patients who have received interferon-alpha within 30 days prior to Day 1 of PKC412 treatment.
• Patients who have received hematopoietic growth factor support within 14 days of Day 1 of PKC412 treatment.
• Glucocorticoids should be tapered off within 14 days of Day 1 of PKC412 treatment if it is anticipated that patients can be tapered off these drugs. Otherwise, for glucocorticoid-requiring patients, investigators should attempt to taper to the minimal dose possible at the time of PKC412 start on day 1.
• Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of PKC412 treatment.
• Patients unwilling or unable to comply with the protocol.
• Patients with known malignant disease involving the central nervous system.
• Patient with any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks. However, if a patient has a pleural effusion which is considered related to systemic mastocytosis (e.g. secondary to ascites) and not causing symptomatic respiratory complaints, the patient may be eligible after discussion with the sponsor.